Research in cancer and other fields has shown that several complex, heretofore insoluble problems in biology and disease could be resolved by a deeper understanding of how cellular intermediary metabolism feeds back to influence the regulatory state. The role of fundamental processes of cellular intermediary metabolism in hypertension, however, remains largely unexplored. We recently discovered a potential role of fumarase and fumaric acid metabolism in hypertension in the Dahl salt-sensitive (SS) rat, a widely used model of human salt-sensitive forms of hypertension. Fumarase catalyzes the conversion of fumaric acid to L-malic acid in the tricarboxylic acid cycle in mitochondria. Fumarase or fumaric acid metabolism was not known to play a role in hypertension. Our recent findings suggest a completely novel mechanism in which fumarase insufficiency and fumaric acid excess contribute to the development of salt-sensitive hypertension. It remains unknown 1) whether specific elevation of fumarase activity in the SS rat would attenuate salt-sensitive hypertension; 2) whether fumarase protects against hypertension in different salt-insensitive strains; and 3) what mechanisms lead to fumarase insufficiency in the SS rat or mediate its hypertensive effect. These questions are critical for rigorously assessing the novel role of fumarase insufficiency in hypertension and understanding the mechanisms involved. We propose experiments towards four specific aims to test several specific hypotheses that address the causal contribution of fumarase insufficiency to the development of hypertension in the SS rat and the mechanisms involved. Aim 1 will test the hypothesis that transgenic elevation of fumarase activity will attenuate salt-induced hypertension in SS rats. Aim 2 will test the hypothesis that fumarase in the renal medulla contributes to protecting Sprague Dawley (SD) rats, SS.13BN rats, and fumarase transgenic SSTgFh1 rats from hypertension. Aim 3 will examine physiological and biochemical mechanisms mediating the hypertensive effect of fumarase insufficiency. Aim 4 will examine molecular mechanisms causing fumarase insufficiency in the SS rat. Project 3 will synergize with other projects in this PPG by exploring mechanisms of hypertension that converge in part via excess medullary H2O2 in the kidney. Project 3 will rely heavily on the biochemistry and animal expertise in the Cores. The study proposed in Project 3 is expected to provide novel insights into the mechanisms underlying the development of salt-sensitive hypertension in the SS rat and drive forward hypertension research in a new direction centered on the largely unexplored role of fundamental processes of cellular metabolism.